Twenty-two percent of the U.S. adult population has antibodies to herpes simplex virus type 2 (HSV-2), indicating chronic infection with the most common virus causing genital herpes. Strategies for the prevention of HSV-2 transmission among sexually active persons remain limited and appear only partially protective. Such strategies include both biomedical (antiviral therapy of the source partner) and behavioral, such as condom use, disclosure of HSV-2 serostatus, and limiting the frequency of sexual encounters or the number of partners. Daily treatment of source partners with valacyclovir in a placebo-controlled trial in HSV-2 discordant couples decreased transmission by 50%. However, a person taking daily antiviral suppressive therapy to reduce the risk of transmission might be less likely to disclose their HSV status to a partner or use condoms, and/or have more frequent sexual encounters or more sexual partners. Thus, on a population basis the beneficial effect of source partner suppressive therapy in reducing transmission could potentially be outweighed by a detrimental effect on sexual behavior. If no such detrimental effect were found, and if acceptability and adherence to daily suppressive therapy for transmission prevention were high, then this prevention modality could be promoted with increased confidence. We plan to conduct an open-label randomized clinical trial of daily suppressive acyclovir versus episodic acyclovir for treatment of genital herpes recurrences among HSV-2 seropositive heterosexual men and women. We hypothesize that HSV-2 seropositive single heterosexuals randomized to antiviral suppressive therapy will be no more likely to engage in risky sexual behavior than those randomized to episodic treatment, and that adherence to suppressive therapy will be high. Participants will be followed for 1 year to assess disclosure of HSV-2 status to sex partners, number of sex partners, frequency of sexual activity, condom use, and adherence to therapy. These outcomes will be measured by self-report in a confidential, computer-based assessment, supplemented by pill counts for adherence. We will then model the potentially conflicting effects of suppressive therapy and sexual behavior change on population-level prevalence of HSV-2. This project, combined with related career development activities, will enable the Principal Investigator to gain valuable clinical trial experience and achieve independence as a clinical researcher in the field of sexually transmitted diseases.